Protein tyrosine phosphatases (PTP) play a critical role in transduction in numerous signal pathways, regulation of cellular functions and immune response. Of the family of PTP's, PTP1B has emerged as a particularly interesting possible target because it is overexpressed in several human diseases. As an intracellular PTP, it is implicated in the regulation of insulin sensitivity through dephosphorylation of the insulin receptor (Elchebly et al, (1999) Science 283(5407), 1544-1548, Klaman et al (2000) Molecular and Cellular Biology 20(15), 5479-5489). PTP1B−/− knockout mice exhibit lower blood glucose and lower insulin concentrations after feeding as well as greater sensitivity to insulin injections. These results suggest that PTP1B is a therapeutic target for type 2 diabetes. A recent report of early phase II clinical trials by Isis Pharmaceuticals using PTP1B mRNA-targeted antisense oligonucleotides indicates that targeting PTP1B proteins can be therapeutically beneficial in type 2 diabetic patients (Havel et al (2007), American Diabetes Association 67th Scientific Sessions, Chicago, Ill.). Additionally, PTP1B-deficient mice are also resistant to weight gain under conditions that would normally lead to obesity, likely due to dephosphorylation of JAK2 by PTP1B resulting in increased leptin sensitivity (Zabolotny et al (2002) Developmental cell 2(4), 489-495; Bence et al (2006) Nature medicine 12(8), 917-924; Cheng et al (2002) Developmental cell 2(4), 497-503). Furthermore, it has been recently shown that deletion of PTP1B activity in transgenic mice bred to develop mammary tumors results in significant increases in tumor latency and resistance to lung metastasis (Julien, S. G. et al (2007) Nature genetics 39(3), 338-346).
Although some progress has been made in the study of the structure, catalytic mechanism, regulation, and localization of the general class of protein tyrosine phosphatases, the inhibitors of PTP1B that have been discovered so far have shown significant limitations. For example, there has been very limited success to date in achieving high selectivity with respect to T-cell phosphatase (TC-PTP), which is nearly identical to PTP1B. Thus, there remains a need for potent and selective PTP inhibitors in general and PTP1B inhibitors specifically.